Relationship between chemical reactions and antitumor activities of bis(haloalkyl)piperidine derivatives (author's transl)

Abstract

Bis (haloalkyl) piperidine (CAP) derivatives were studied with respect to the relationship among their mode of hydrolysis in a bicarbonate buffered solution, their reactivity with Na2S2O3 or 4-(p-nitrobenzyl) pyridine, and their antitumor activity on Ehrlich ascites carcinoma and rat ascites hepatoma AH-13. It was deduced that CAP derivatives rapidly formed intramolucular cyclic intermediates, an ethylene imine from the secondary amines and an ethylene imonium ion from the tertiary amines, in the process of hydrolysis. Moreover, the reactivity of these compounds was in the order of 1-methyl-2, 6-bis (halomethyl) piperidines>1-(β-haloethyl)-2-halomethylpiperidines>1-(γ-halopropyl)-2-halomethylpiperidines>2, 6-bis (halomethyl) piperidines, but there was no parallelism between the chemical reactivity and the antitumor activity. However, a significant correlation was observed between the cytotoxicity of the tertiary amine type CAP derivatives proceeded by a similar mechanism of reaction, EC50 against Ehrlich ascites carcinoma cells or IC50 against AH-13 cells, and the ratio of the rate constant of halogen ion release, k1', to the rate constant of disapperance of alkylating active compounds, -k", from these amines, -k1'/k", which seemed to be a durability of alkylating activity. On the other hand, 1-(γ-halopropyl)-2-halomethylpiperidines which showed a monofunctional chemical reaction only provided with a high therapeutic index, LD50/ED50, on AH-13 bearing rats, which was equal to those of cyclophosphamide and nitrogen mustard N-oxide.